High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis

Abstract

<h3>Objective</h3> We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards. <h3>Methods</h3> Using an immunoprecipitation and liquid chromatography–mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan. <h3>Results</h3> Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82–0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79–0.92). The combination of plasma Aβ42/Aβ40, age, and <i>APOE</i> ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90–0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (&lt;0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (<i>p</i> = 0.01). <h3>Conclusions</h3> Plasma Aβ42/Aβ40, especially when combined with age and <i>APOE</i> ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia. <h3>Classification of evidence</h3> This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.